Evidence is mounting that diabetes is associated with a higher risk for developing breast cancer and poor breast cancer prognosis and outcomes compared to non-disease women. With more than 200,000 new cases of breast cancer diagnosed annually in the US and more than 40,000 women dying each year from breast cancer, we cannot afford to see a rise in breast cancer cases nor a setback in prognosis as diabetes reaches burgeoning levels worldwide. Metformin, an insulin-lowering agent used in first-line treatment of diabetes, shows great promise for reducing both breast cancer risk and improving prognosis among women with diabetes. Laboratory studies support a chemopreventive effect as do the limited number of observational studies. For the millions of women suffering from diabetes in the US and at risk for breast cancer, research is needed to disentangle this complex relationship. Leveraging rich electronic data sources from the defined population of Group Health Cooperative, we propose to comprehensively investigate the association between use of metformin and incident invasive breast cancer risk among a large cohort of women diagnosed with diabetes from 1996-2010. An important element of the proposed study is our unique opportunity to also investigate the effect of duration of metformin use, recency of use, and effect modifiers such as age, menopausal status, obesity, and duration of diabetes. In addition, we propose to assess any differences in stage and histology by metformin use. Because selecting the most appropriate medication(s) to treat the already complicated disease of diabetes is a challenge for health care providers and patients, we will also compare risk of incident breast cancer across other diabetic medication groups and combinations. The robust study proposed is an important part of the effort to understand the etiology of breast cancer and an opportunity to increase prevention among the growing numbers of women with diabetes. We anticipate the evidence from the proposed study will be used to inform the need for a clinical trial of metformin as a chemopreventive therapy in women with diabetes as well as assist providers and patients in making better informed decisions when weighing the risk and benefits of the many available diabetes medications. Dissemination of findings that metformin is associated with a reduction in breast cancer would likely increase uptake of metformin which could result in improved morbidity and mortality due to both diabetes and cancer.